Extracellular signal regulated kinase½ (ERK1/2) signaling is critical to endothelin-1 (ET-1)-induced cardiomyocyte
hypertrophy. This study was to investigate ERK1/2 signaling and hypertrophic response to ET-1 stimulation in
cardiomyocytes (CMs) from spontaneous hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Primary
neonatal SHR and WKY CMs were exposed to ET-1 for up to 24 hrs. Minimal basal ERK1/2 phosphorylation was present
in WKY CMs, while a significant baseline ERK1/2 phosphorylation was observed in SHR CMs. ET-1 induced a time- and
dose-dependent increase in ERK1/2 phosphorylation in both SHR and WKY CMs. However, ET-1-induced ERK1/2 activation
occurred much earlier with significantly higher peak phosphorylation level, and stayed elevated for longer duration
in SHR CMs than that in WKY CMs. ET-1-induced hypertrophic response was more prominent in SHR CMs than that in
WKY CMs as reflected by increased cell surface area, intracellular actin density, and protein synthesis. Pre-treatment with
ERK1/2 phosphorylation inhibitor PD98059 completely prevented ET-1-induced ERK1/2 phosphorylation and increases
in cell surface area and protein synthesis in SHR and WKY CMs. The specific PI3 kinase inhibitor LY294002 blocked
ET-1-induced Akt and ERK1/2 phosphorylation, and protein synthesis in CMs. These data indicated that ERK1/2 signaling
was differentially enhanced in CMs, and was associated with increased cardiac hypertrophic response to ET-1 in SHR.
ET-1-induced ERK1/2 activation and cardiac hypertrophy appeared to be mediated via PI3 kinase/Akt signaling in SHR
and WKY. The differential ERK1/2 activation in SHR CMs by ET-1 might represent a potential target for combination
therapy of hypertension.
Keywords: Akt, cardiomyocyte hypertrophy, endothelin, ERK1/2, hypertension, spontaneous hypertensive rat.
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